title: Erythrocyte promotion of platelet reactivity decreases the effectiveness of aspirin as an antithrombotic therapeutic modality: the effect of low-dose aspirin is less than optimal in patients with vascular disease due to prothrombotic effects of erythrocytes on platelet reactivity.
abstract: BACKGROUND
  Aspirin (acetylsalicylic acid, ASA) is widely used for secondary prevention of ischemic vascular events, although its protection only occurs in 25% of patients. We previously demonstrated that platelet reactivity is enhanced by a prothrombotic effect of erythrocytes in a thromboxane-independent manner. This diminishes the antithrombotic therapeutic potential of ASA. Recent data from our laboratory indicate that the prothrombotic effect of erythrocytes also contains an ASA-sensitive component. In accordance with this observation, intermittent treatment with high-dose ASA reduced the prothrombotic effects of erythrocytes ex vivo in healthy volunteers. In the present study, the effects of platelet-erythrocyte interactions were evaluated ex vivo in 82 patients with vascular disease: 62 patients with ischemic heart disease treated with 200 mg ASA/d and 20 patients with ischemic stroke treated with 300 mg ASA/d.
  
  
  RESULTS
  Platelet activation (release reaction) and platelet recruitment (fluid-phase proaggregatory activity of cell-free releasates from activated platelets) were assessed after collagen stimulation (1 microg/mL) of platelets, platelet-erythrocyte mixtures, or whole blood. Platelet thromboxane A2 synthesis was inhibited by >94% by ASA administration in all patients. Importantly, platelet recruitment followed one of three distinct patterns. In group A (n=32; 39%), platelet recruitment was blocked by ASA both in the presence and absence of erythrocytes. In group B (n=37; 45%), recruitment was abolished when platelets were evaluated alone but continued in the presence of erythrocytes, indicating a suboptimal effect of ASA on erythrocytes of this patient group. In group C (n= 13; 16%), detectable recruitment in stimulated platelets alone persisted and was markedly enhanced by the presence of erythrocytes.
  
  
  CONCLUSIONS
  In two thirds of a group of patients with vascular disease, 200 to 300 mg ASA was insufficient to block platelet reactivity in the presence of erythrocytes despite abolishing thromboxane A2 synthesis. Platelet activation in the presence of erythrocytes can induce the release reaction and generate biologically active products that recruit additional platelets into a developing thrombus. Insufficient blockade of this proaggregatory property of erythrocytes can lead to development of additional ischemic complications.
authors.affiliation: Research Center, University Hospital La Fe, Valencia, Spain. mteresas@san.gva.es
authors.forename: J
authors.initials: J
authors.lastname: Valles
authors.forename: M T
authors.initials: MT
authors.lastname: Santos
authors.forename: J
authors.initials: J
authors.lastname: Aznar
authors.forename: A
authors.initials: A
authors.lastname: Osa
authors.forename: A
authors.initials: A
authors.lastname: Lago
authors.forename: J
authors.initials: J
authors.lastname: Cosin
authors.forename: E
authors.initials: E
authors.lastname: Sanchez
authors.forename: M J
authors.initials: MJ
authors.lastname: Broekman
authors.forename: A J
authors.initials: AJ
authors.lastname: Marcus
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001241:Aspirin / Q000008:administration & dosage / Q000627:therapeutic use*; D001792:Blood Platelets / Q000378:metabolism / Q000502:physiology*; D002545:Brain Ischemia / Q000188:drug therapy; D002561:Cerebrovascular Disorders / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects / Q000502:physiology*; D005260:Female; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000188:drug therapy; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D012701:Serotonin / Q000378:metabolism; D014652:Vascular Diseases / Q000097:blood / Q000188:drug therapy* / Q000209:etiology*
chemical_list: D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors; D012701:Serotonin; D001241:Aspirin